Paclitaxel, having a chemical name of 5β-20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-on,4,10 diacetate 2-benzate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine, is a naturally occurring compound which has shown great promise as an anti-cancer drug. It is a unique diterpene compound derived from the bark of the Taxus brevifolia (Pacific yew) tree. As early as in 1971, paclitaxel was discovered in the crude extract of the bark of the yew tree through a routine preclinical tumor screening program at the National Cancer Institute of the National Institutes of Health, and found to be an effective antileukemic and antitumor agent. See Wani et al, Plant antitumor agents, VI: The Isolation and Structure of Paclitaxel, a Novel Antileukemic and Antitumor Agent from Taxus brevifolia, J. Am. Chem. Soc., 93:2325-2327 (1971).
Paclitaxel inhibits rapidly dividing cancer cells by stabilizing microtubule during the cell division and arresting the mitotic spindles. The cancer cells are arrested in the G2 or M phases until the cancer cell death. While most of the well-known mitotic spindle poisons (such as colchicines and podophyllotoxin) inhibit microtubule assembly, paclitaxel employs a different mechanism of action by shifting the equilibrium of polymerimization/depolymerization toward polymer assembly and stabilizing microtubules against depolymerization under conditions which would cause rapid disaggregation of microbubules. The interference with the polymerization/depolymerization cycle in cells appears to interfere with both the relication and migration of cells. Paclitaxel has demonstrated good response rates in treating both ovarian and breast cancer patients and has shown encouraging results in patients with other types cancer including lung, melanoma, lymphoma, head and neck.
Paclitaxel is poorly soluble in water (less than 0.01 mg/mL) and other common vehicles used for the parenteral administration of drugs. Certain organic solvents, however, may at least partially dissolve paclitaxel. However, when a water-miscible organic solvent containing paclitaxel at near its saturation solubility is diluted with aqueous infusion fluid, the drug may precipitate.
Consequently, the commercial products of paclitaxel incorporate a co-solvent system containing a mixture of a polar solvent and a non-ionic solvent, such as a mixture of a polyethylene glycol and Cremophor® EL. Cremophor® EL is the tradename of a condensation product of castor oil and ethylene oxide sold by BASF (Badische Anilin und Soda Fabrik AG, Ludwigshafen, Federal Republic of Germany). Another suitable co-solvent system for paclitaxel is a 50:50 mixture of ethanol and Cremophor® EL. At the present time, PDR (Physicians Desk Reference) recommends that paclitaxel be dissolved in 52.7% Cremophor® EL 49.7% (v/v) dehydrated alcohol, and further diluted in NS (normal saline) or D5W (5% dextrose in water) to a final concentration of 5% Cremophor® EL and 5% dehydrated alcohol or less, for the intravenous administration of the drug to humans.
Paclitaxel for injection concentrate is currently available from Bristol-Myers Squibb Co. (New York, N.Y.) in 30-mg (5-mL) single-dose vials. Each milliliter of formulation contains approximately 6 mg Paclitaxel, 527 mg of Cremophor® EL, and 49.7% (v/v) dehydrated alcohol. This concentrated formulation must be further diluted with NS, D5W, D5NS (normal saline, 5% dextrose in water and 5% dextrose in normal saline) or D5W-R (Ringer's solution with 5% dextrose in water) prior to administration.
It has been noted that the Cremophor/ethanol formulation of paclitaxel precipitates upon dilution with infusion fluid, and fibrous precipitates formed in some compositions during storage for extended periods of time. (See U.S. Pat. No. 5,504,102). Thus, although the ethanol and Cremophor® EL co-solvent system is effective in solubilizing sufficient amounts of the paclitaxel, the resulting composition has been shown to have a limited shelf life. During storage for extended periods of time, the potency or pharmaceutical activity of the composition can decrease as much as 60%.
It has also been discovered that the commercial grade Cremophor® EL with ethanol as a co-solvent, although effective in solubilizing pharmaceutical agents, produces injection compositions that exhibit instability over extended periods of time. In particular, paclitaxel in 52.7 mg/mL:49.7% of Cremophor® EL and dehydrated ethanol exhibit a 13.3% loss of potency after storage at 40° C. for 7 days (See U.S. Pat. No. 6,140,359) and a loss of potency of greater than 60% after storage for 12 weeks at 50° C. and a loss of potency to 86.7% at 40° C. for seven days (See U.S. Pat. No. 6,140,359). The loss of potency is attributed to the decomposition of paclitaxel during storage.
It is, therefore, a need for a paclitaxel formulation to overcome the stability problems associated with conventional paclitaxel formulations as noted above and as known to one of skill in the art. Recently, U.S. Pat. No. 5,504,102 discloses a way to reduce the decomposition of paclitaxel in Cremophor® EL by reducing the carboxylate anion content with an aluminum oxide bed or by the addition of an acid and particularly a mineral acid such as HCl or HNO3. It is believed that the carboxylate anions in Cremophor® EL cause the degradation of paclitaxel.
U.S. Pat. Nos. 5,733,888, 5,972,992, 5,977,164, and 6,140,359 similarly disclose that the addition of an acidifying agent to polyoxyethylated castor oil to a pH of less than 8.1 and preferably within a pH range of 5 to 7 can prolong the shelf life of a paclitaxel formulation. The preferred acidifying agent is an anhydrous citric acid.
In the invention to be described in the following sections, a novel injectable pharmaceutical composition (i.e., paclitaxel aqueous injection solution) is described. The injectable pharmaceutical composition differs from other paclitaxel aqueous injection solutions currently commercially available in two major aspects: first, it contains a small amount of water in the formulation, as opposed to no water in the commercially available products; and second, the injectable pharmaceutical composition of the present invention is infused with CO2, which can be converted into carbonate ions in the aqueous solution, which in turn act to reduce the pH of the injectable aqueous solution to about ≦5.0. The novel injectable pharmaceutical composition of the present invention demonstrates improved stability and safety as well as prolonged shelf-life for paclitaxel.